Genetic and clinical analyses in an Italian series of idiopathic hypogonadotropic hypogonadism
Marco Bonomi1, Francesco Antonica1, Anna Cariboni2, Marta Busnelli1, Anna Pia3, Giorgio Borretta3, Paolo Beck-Peccoz1, Csilla Krausz4, Roberto Maggi2 & Luca Persani1
Idiopathic hypogonadotropic hypogonadism (IHH) is a rare and heterogeneous disease due to defects of GnRH secretion or action. IHH could be associated or not with anosmia respectively identifying the Kallmanns syndrome (KS) or the normosmic IHH (nIHH). So far numerous causative genetic defects have been described, but very recent molecular genetic studies and animal models have opened novel perspectives. We are studying a series of 16 KS (14M,2F) and 18 nIHH (14M,4F). All patients have normal karyotype, low/normal gonadotropins in the presence of low sex-steroid levels and a blunted LH/FSH response after GnRH injection. FGFR1, Ebf2, PROK2, PROKR2 genes were examined in all cases whereas GnRHR and GPR54 gene analysis was limited to nIHH. The coding sequences of GnRHR, Ebf2 and GPR54 showed no abnormalities. Two novel mutations of PROKR2 (V158I, V334M) and one of PROK2 (G62D) gene were found in 1 nIHH female, 1 KS male patients and 1 nIHH male patient, respectively. The analysis of FGFR1 gene showed results of particular interest. The mutation D200E was found in two unrelated patients discordant for osmic function and bimanual synkynesia. The mutation F210X was instead found in 1 nIHH male patient that did not undergo puberty. This patient had a brother also affected with nIHH and absent pubertal development that was found to carry the same mutation. This mutation was therefore inherited from one of the parents who had had a normal puberty and was still unaffected at an age beyond 30 years. These variations are present in the heterozygous state in the patients according to the reported mechanism of haplo-insufficiency. The variable neurological phenotype (osmic function and bimanual synkynesia) associated with the same FGFR1 mutation and the highly variable IHH penetrance in our family represents additional arguments in favour of a multiple genetic origin of these defects.